Process for annealing amorphous atorvastatin

ABSTRACT

Processes for annealing amorphous atorvastatin is described. Pharmaceutical compositions and formulations containing annealed amorphous atorvastatin are also described.

This application is a continuation application of U.S. Ser. No.14/688,451 filed Apr. 16, 2015, now pending which is a divisionalapplication of U.S. Ser. No. 12/067,056 filed Aug. 19, 2008, now U.S.Pat. No. 9,034,913, which is a 371 application of PCT/IB2006/002648filed on Sep. 11, 2006, which claims the benefit of provisionalapplication U.S. Ser. No. 60/758,270 filed on Jan. 10, 2006 andprovisional application U.S. Ser. No. 60/719,258 filed on Sep. 21, 2005,all of which are incorporated herein by reference in their entirety

FIELD OF THE INVENTION

The invention relates to processes for annealing amorphous atorvastatinas well as compositions and pharmaceutical formulations containingannealed amorphous atorvastatin. The annealed amorphous atorvastatin ismore stable than amorphous atorvastatin that has not been annealed.

BACKGROUND OF THE INVENTION

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) tomevalonate is an early and rate-limiting step in the cholesterolbiosynthetic pathway. This step is catalyzed by the enzyme HMG-CoAreductase. Statins inhibit HMG-CoA reductase from catalyzing thisconversion. As such, statins are collectively potent lipid loweringagents.

Atorvastatin and pharmaceutically acceptable salts thereof areselective, competitive inhibitors of HMG-CoA reductase. Atorvastatincalcium is currently sold as LIPITOR® having the chemical name[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1) trihydrate and the formula

As such, atorvastatin calcium is a potent lipid-lowering compound and isthus useful as a hypolipidemic and/or hypocholesterolemic agent.Atorvastatin calcium is also useful in the treatment of osteoporosis,benign prostatic hyperplasia (BPH) and Alzheimer's disease.

A number of patents and published International Patent Applications haveissued describing atorvastatin, formulations of atorvastatin, as well asprocesses and key intermediates for preparing atorvastatin. Theseinclude: U.S. Pat. Nos. 4,681,893; 5,273,995; 5,003,080; 5,097,045;5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047;5,248,793; 5,280,126; 5,397,792; 5,342,952; 5,298,627; 5,446,054;5,470,981; 5,489,690; 5,489,691; 5,510,488; 5,686,104; 5,969,156;5,998,633; 6,087,511; 6,121,461; 6,126,971; 6,433,213; 6,476,235;6,605,759; WO 01/36384; WO 02/41834; WO 02/43667; WO 02/43732; WO02/051804; WO 02/057228; WO 02/057229; WO 02/057274; WO 02/059087; WO02/083637; WO 02/083638; WO 03/011826; WO 03/050085; WO 03/07072; and WO04/022053.

It has been described that the amorphous forms of a number of drugsexhibit different dissolution characteristics and in some casesdifferent bioavailability patterns compared to the crystalline form(Konno T., Chem. Pharm. Bull., 1990; 38:2003-2007). For some therapeuticindications, one bioavailability pattern may be favored over another.

Variations in dissolution rates can make it advantageous to produceatorvastatin formulations in either crystalline or amorphous forms. Forexample, for some potential uses of atorvastatin (e.g., acute treatmentof patients having strokes as described in Takemoto, M.; Node, K.;Nakagami, H.; Liao, Y.; Grimm; M.; Takemoto, Y.; Kitakaze, M.; Liao, J.K., Journal of Clinical Investigation, 2001; 108(10): 1429-1437), arapid onset of activity may be highly beneficial in improving theefficacy of atorvastatin.

The preparation of amorphous atorvastatin has been previously described.For example, Lin et al., U.S. Pat. No. 6,087,511, describe formingamorphous atorvastatin from crystalline atorvastatin. To form amorphousatorvastatin, Lin et al. describe that crystalline atorvastatin isdissolved in a non-hydroxylic solvent such as tetrahydrofuran. Thenon-hydroxylic solvent is removed to produce a brittle foam that isbroken up by mechanical agitation to afford amorphous atorvastatin.

WO 00/71116 also describes forming amorphous atorvastatin using anon-hydroxylic solvent.

WO 01/28999 describes a process for forming amorphous atorvastatincalcium by recrystallization of crude atorvastatin from an organicsolvent which comprises dissolving crude amorphous atorvastatin calciumin a lower alkanol containing 2-4 carbon atoms or a mixture of suchalkanols under heating and isolating the amorphous atorvastatin calciumprecipitated after cooling.

WO 01/42209 describes preparing amorphous atorvastatin by precipitatingthe atorvastatin using a solvent in which atorvastatin is insoluble orvery slightly soluble, from a solution of atorvastatin which is providedwith a solvent in which atorvastatin is freely soluble. Preferredsolvents in which atorvastatin is freely soluble include low molecularweight alcohols, e.g. methanol and ethanol.

WO 03/078379 describes forming amorphous atorvastatin by dissolvingatorvastatin in a hydroxylic solvent and removing the solvent by eitherfreeze-drying or spray drying.

US Published Patent Application 2004/0024046 A1 describes a process forforming amorphous atorvastatin by precipitating atorvastatin from asolution with a solvent in which atorvastatin is insoluble or veryslightly soluble.

The use of amorphous pharmaceutical substances, such as amorphousatorvastatin calcium, can be beneficial because such disorderedmaterials usually have higher solubility and bioavailability. However,an unsatisfactory characteristic shared by amorphous drug substances isthat they usually have lower physical and chemical stabilities, thusreducing their shelf life over crystalline drug substances. Thus,amorphous atorvastatin is susceptible to degradation upon storage. Oncedegraded, the drug material may not be acceptable for some medical uses.As a result, there is a need to develop methods for stabilizingamorphous atorvastatin.

SUMMARY OF THE INVENTION

These and other needs are met by the present invention which is directedto a method for annealing amorphous atorvastatin, either alone or aspart of a pharmaceutical composition/formulation, each as describedherein. By annealing amorphous atorvastatin according to the proceduredeveloped by the inventors and described herein leads to surprisinglyhigher levels of improved stability compared to non-annealed amorphousatorvastatin samples; that is, annealed atorvastatin samples had a lowerrate of chemical degradation compared to non-annealed samples. Thus,annealed amorphous atorvastatin can be stored for longer periods thannon-annealed amorphous atorvastatin, and can be used to preparepharmaceutical dosage forms with enhanced stability profiles as comparedto dosage forms containing non-annealed amorphous atorvastatin.

Thus, the Invention is directed to a process for annealing amorphousatorvastatin at elevated temperature comprising heating at ambientpressure amorphous atorvastatin in an essentially solvent-free system toa temperature of between approximately 50° C. to approximately 140° C.;holding the temperature for approximately 1 minute to approximately 30days to provide the annealed amorphous atorvastatin; and cooling theresulting annealed amorphous atorvastatin. In one embodiment, the timeis as provided earlier and the temperature is between approximately 80°C. to approximately 110° C. In another embodiment, the time is asprovided earlier and the temperature is between approximately 90° C. toapproximately 105° C. In another embodiment, the temperature is asprovided earlier and the time is between approximately 10 minutes andapproximately 72 hours. In another embodiment, the temperature is asprovided earlier and the time is between approximately 30 minutes andapproximately 12 hours. In a preferred embodiment, the temperature is asprovided earlier wherein the time is between approximately 1 and 6hours.

The invention is also directed to a process for annealing amorphousatorvastatin at elevated or high pressure. According to the invention,such a process comprises treating amorphous atorvastatin at a pressureof between approximately 0.1 kBar to approximately 250 kBar at atemperature of between ambient temperature (approximately 20° C.) toapproximately 150° C. for approximately 1 minute to approximately 30days. In one embodiment, the temperature and time are as providedearlier and the pressure is between approximately 0.5 kBar andapproximately 200 kBar. In one embodiment, the temperature and time areas provided earlier and the pressure is between approximately 0.5 kBarand approximately 10 kBar. In another embodiment, the pressure and timeare as provided earlier and the temperature is between approximately 25°C. to approximately 80° C. In another embodiment, the pressure andtemperature are as provided earlier and the time is betweenapproximately 30 minutes and approximately 12 hours. In anotherembodiment, the temperature and time are as provided earlier and thepressure is cycled between about ambient pressure and about 200 kBarstwo or more times. As would be understood by one of ordinary skill inthe art, elevated pressures may be achieved using techniques known inthe art.

The invention is also directed to a process for annealing amorphousatorvastatin comprising irradiating amorphous atorvastatin withmicrowave at a frequency ranging from about 1 GHz to about 100 GHz andpower of about 1 watt (W) to about 3000 watts (W) either in a continuousor pulse mode for a time period ranging from about 1 second to about 10hours. In one embodiment, amorphous atorvastatin is irradiated withmicrowave frequency of about 2.45 GHz and power of about 10 W to about500 W in a continuous mode range for a time period of about 10 secondsup to about 10 hours. In another embodiment, amorphous atorvastatin isirradiated from about 1 minute up to about 10 hours with microwave at afrequency of about 2.45 GHz and power of about 1 W to about 3000 W in apulse mode range for a pulse time period of about 10 to about 600seconds.

The invention is also directed to a process for annealing amorphousatorvastatin comprising irradiating amorphous atorvastatin withultrasound at a frequency ranging from about 15 KHz to about 40 KHz andpower of about 100 watts (W) to 4000 watts (W) either in a continuous orpulse for a time period ranging from about 1 second to about 10 hours.In one embodiment, amorphous atorvastatin is irradiated with ultrasoundat a frequency of about 15 KHz to about 40 KHz and power of about 100 Wto 3000 W in a continuous mode range for a time period of about 10seconds up to about 10 hours. In another embodiment, amorphousatorvastatin is irradiated from about 1 minute up to about 10 hours withultrasound at a frequency of about 20-35 KHz and power of about 100 W to3000 W in a pulse mode range for a pulse time period of about 10 toabout 600 seconds.

The Invention is also directed to the annealing processes describedabove, wherein the amorphous atorvastatin is part of a pharmaceuticalcomposition or formulation prior to the annealing process being applied,each as described herein. For example, amorphous atorvastatin can beadmixed with a pharmaceutically acceptable diluent, carrier, orexcipient to form, by way of example, a tablet. The tablet can thenundergo an annealing process described herein.

As described above, amorphous atorvastatin, either alone or as part of apharmaceutical composition/formulation, is annealed by temperature,pressure, microwave or ultrasound, each as described herein. Temperatureannealing as described herein may be accomplished by any methodavailable to the skilled artisan, for instance, by using an oven. Forexample, the samples are heated to a certain temperature for set periodsof time, each as described herein, and then withdrawn from the oven andallowed to cool to room temperature. Irradiation may be accomplished by,for example, using a microwave oven whereas pressure and ultrasoundtreatment can be applied using, for example, an ultrasound probe.

According to the invention, an annealing process as described herein canbe repeated two or more times.

Also according to the invention, an annealing process as describedherein can be performed under an inert atmosphere (i.e., at a reducedoxygen partial pressure) such as nitrogen or under vacuum, in order tominimize degradation during annealing.

According to the invention, amorphous atorvastatin may be exposed to aplasticizer through either gas or liquid phase, either prior to orduring an annealing process, each as described herein. With treatmentwith a plasticizer, an annealing process may be conducted under milderconditions (e.g., lower temperature for thermal/temperature annealing,or lower power for microwave annealing), each as described herein, andthus minimize degradation while still providing the appropriate extentor degree of annealing.

Also according to the invention, amorphous atorvastatin, either alone oras part of a pharmaceutical composition/formulation, may be annealed bytwo or more annealing processes, each as described herein,simultaneously or consecutively.

Further, the stability of the resulting annealed amorphous atorvastatincan be evaluated. For example, the annealed amorphous atorvastatin canbe placed in screw top vials and incubated in a 50° C./20% relativehumidity (“RH”) chamber and then analyzed according to techniquesavailable to the skilled artisan as described in Example 1.

The Invention is further directed to a composition of matter which isannealed amorphous atorvastatin.

The invention is further directed to annealed amorphous atorvastatin,either alone or as part of a pharmaceutical composition/formulation,prepared by a process as described herein.

The invention is additionally directed to a pharmaceutical compositionor formulation comprising annealed amorphous atorvastatin admixed with apharmaceutically acceptable diluent, carrier, or excipient.

The invention is additionally directed to a pharmaceutical compositionor formulation comprising annealed amorphous atorvastatin; at least onepharmaceutically acceptable alkali metal or alkaline earth metal salt(e.g., sodium carbonate, calcium carbonate, calcium hydroxide, magnesiumcarbonate, magnesium hydroxide, magnesium silicate, magnesium aluminateor aluminum magnesium hydroxide); and a pharmaceutically acceptablediluent, carrier or excipient. Preferably, a pharmaceutical compositionor formulation of the invention is an oral pharmaceutical formulation.

As would be understood by one of skill in the art, methods for thepreparation of a pharmaceutical composition or formulation suitable forthe delivery of annealed amorphous atorvastatin may be found, forexample, in Remington's Pharmaceutical Sciences, 19th Edition (MackPublishing Company, 1995), or as provided below for formulations fororal administration. For example, a pharmaceutical composition orformulation containing amorphous atorvastatin can be prepared by anymeans known in the art including, but not limited to, admixing amorphousatorvastatin with a pharmaceutically acceptable diluent, carrier orexcipient and, optionally, at least one pharmaceutically acceptablealkaline earth metal salt, each as described herein.

The annealed amorphous atorvastatin may be administered alone or incombination with one or more other drugs (or as any combinationthereof). Generally, the annealed amorphous atorvastatin, whether aloneor in combination, will be administered as a formulation in associationwith one or more pharmaceutically acceptable diluents, carriers orexcipients. The terms “diluent”, “carrier” and “excipient” may be anydiluent, carrier or excipient known in the art including those describedin, for example, Remington's Pharmaceutical Sciences, Mack PublishingCo., (A. R. Gennaro edit 1985). As would be understood by one of skillin the art, the choice of diluent, carrier or excipient will to a largeextent depend on factors such as the particular mode of administration,the effect of the excipient on solubility and stability, and the natureof the dosage form.

Alternatively, a formulation or composition comprising the annealedamorphous atorvastatin may be stabilized by further comprising at leastone pharmaceutically acceptable alkali metal or alkaline earth metalsalt such as, but not limited to, those provided in U.S. Pat. Nos.5,686,104 and 6,126,971, both of which are assigned to the assignee ofthe Instant application. The alkali metal or alkaline earth metal saltis preferably sodium carbonate, calcium carbonate, calcium hydroxide,magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesiumaluminate or aluminum magnesium hydroxide.

Still further, according to the invention, a pharmaceutical formulationof the invention containing amorphous atorvastatin can be annealed atelevated temperature, at elevated pressure, under microwave irradiation,or under ultrasound irradiation, each as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts increases in the level of total degradation productsduring storage of amorphous atorvastatin calcium at 50° C./20% RH (“RH”refers to relative humidity). The four curves are related to the controland samples that were annealed for 1, 6, and 18 hours at 100° C.

FIG. 2 depicts level of total oxidative degradation products as afunction of time during storage of amorphous atorvastatin calcium at 50%C/20% relative humidity. The four curves are related to the control andsamples that were annealed for 1, 6, and 18 hours at 100° C.

FIG. 3 depicts level of degradation product 1 (Scheme 1) as a functionof time during storage of amorphous atorvastatin calcium at 50° C./20%relative humidity. The four curves are related to the control andsamples that were annealed for 1, 6, and 18 hours at 100° C.

FIG. 4 depicts level of degradation product 2 (Scheme 2) as a functionof time during storage of amorphous atorvastatin calcium at 50° C./20%relative humidity. The four curves are related to the control andsamples that were annealed for 1, 6, and 18 hours at 100° C.

FIG. 5 depicts a solid-state ¹⁹F nuclear magnetic resonance (NMR)spectrum of atorvastatin calcium samples from Example 1. A standardspectrum is also shown for comparison.

FIG. 6a depicts the X-ray powder diffraction patterns of spray-driedunannealed (control sample) amorphous atorvastatin calcium.

FIG. 6b depicts the X-ray powder diffraction patterns of spray-driedamorphous atorvastatin calcium that was annealed for 1 hour at 100° C.

FIG. 6c depicts the X-ray powder diffraction patterns of spray-driedamorphous atorvastatin calcium that was annealed for 6 hours at 100° C.

FIG. 6d depicts the X-ray powder diffraction patterns of spray-driedamorphous atorvastatin calcium that was annealed for 18 hours at 100° C.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “atorvastatin” as used herein refers to[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicadd (the free acid form):

and salts, solvates, hydrates and polymorphs thereof. Pharmaceuticallyacceptable base addition salts of atorvastatin can be formed with metals(e.g., alkali metal or alkaline earth metal salts) or amines (e.g.organic amines). Examples of suitable amines include, but are notlimited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine,and procaine (see, for example, Berge, S. M., et al., “PharmaceuticalSalts”, J. of Pharm. Sci., 1977; 66:1).

A preferred form of atorvastatin is atorvastatin calcium; morespecifically, atorvastatin hemi-calcium salt trihydrate and marketedunder the tradename LIPITOR®.

The term “amorphous atorvastatin” as used herein refers to differenttypes of disordered forms of atorvastatin, as described above, includingcompletely amorphous material, partially amorphous material (e.g., amixture of crystalline and amorphous), and crystalline mesophases (e.g.,liquid-crystal type structures). Amorphous atorvastatin, and the amountof amorphous atorvastatin present, may be characterized by techniquesknown in the art such as powder x-ray diffraction, solid-state nuclearmagnetic resonance (SSNMR) spectroscopy, or thermal techniques such asdifferential scanning calorimetry (DSC).

The amorphous atorvastatin used to practice the invention can beprepared by any means known in the art including, but not limited to,those means provided in Lin et al., U.S. Pat. No. 6,087,511, WO00/71116, WO 01/28999, WO 01/42209, WO 03/078379, or US Published PatentApplication 2004/0024046 A1. The amorphous atorvastatin can be preparedby spray-drying or freeze-drying according to the process described in,Published U.S. Patent Application 2005-0032880, and commonly owned, U.S.Provisional Application Ser. No. 60/623,086 field Oct. 28, 2004, or byprecipitation from a solution as described in U.S. ProvisionalApplication Ser. No. 60/562,948 filed Apr. 16, 2004, assigned to thesame assignee as the instant application. The term “freeze-drying”refers to the process of removing a solvent from a frozen product underreduced pressure. The term “spray-drying” means breaking up liquidmixtures into small droplets and rapidly removing solvent from themixture.

The annealed amorphous atorvastatin may also exist in unsolvated andsolvated forms. The term ‘solvate’ is used herein to describe amolecular complex comprising annealed amorphous atorvastatin, asdescribed herein, and one or more pharmaceutically acceptable solventmolecules, for example, ethanol. The term ‘hydrate’ is employed whensaid solvent is water.

The annealed amorphous atorvastatin can be assessed for itsbiopharmaceutical properties, such as solubility and solid state andsolution stability (across pH), permeability, etc., in order to selectthe most appropriate dosage form and route of administration fortreatment of the proposed indication.

“Annealing” refers to (a) heating the amorphous atorvastatin at aspecified temperature, holding the temperature for a set period of time,and then cooling the resulting annealed amorphous atorvastatin; (b)exposing the amorphous atorvastatin to a higher than ambient pressure;(c) irradiating the amorphous atorvastatin with microwave or ultrasoundradiation frequency; or (d) a combination thereof. According to theinvention, annealing (a), (b), (c) and (d) can be performed in eithercontinuous or pulse mode.

The term “essentially solvent-free system” as used herein refers to asystem where no additional solvent is added. The amorphous atorvastatinmay contain residual solvent resulting from its synthesis orpharmaceutical processing operations, e.g., wet granulation. Forexample, amorphous atorvastatin which contains about 2 wt % water oranother solvent would be considered “essentially solvent-free”.

The term “plasticizer” refers to molecules that increase molecularmobility (e.g., decrease glass transition temperature, or thetemperature of the localized motions such as beta-relaxation). Examplesof suitable plasticizers include, but are not limited to, alcohols(e.g., methanol, ethanol, glycerol), esters (e.g., ethyl acetate),ketones (e.g., acetone), and other organic and inorganic solvents (e.g.,water).

Oral Administration

Annealed amorphous atorvastatin may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, and/or buccal, lingual, or sublingualadministration by which the compound enters the blood stream directlyfrom the mouth.

Formulations suitable for oral administration include solid, semi-solidand liquid systems such as tablets; soft or hard capsules containingmulti- or nano-particulates, liquids, or powders; lozenges (includingliquid-filled); chews; gels; fast dispersing dosage forms; films;ovules; sprays; and buccal/mucoadhesive patches.

Alternatively, a composition or formulation of the invention may be inthe form of multiparticulate beads.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen(2001).

For tablet dosage forms, depending on dose, the drug may make up fromabout 1 weight % to about 60 weight % of the dosage form, more typicallyfrom about 5 weight % to about 40 weight % of the dosage form. Inaddition to the drug, tablets generally contain a disintegrant. Examplesof disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, croscarmellose sodium,crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystallinecellulose, lower alkyl-substituted hydroxypropyl cellulose, starch,pregelatinised starch and sodium alginate. Generally, the disintegrantwill comprise from about 1 weight % to about 25 weight %, preferablyfrom about 3 weight % to about 20 weight % of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Typically such tablet formulations contain about 0-10weight % binder. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate. Tablets mayalso optionally comprise stabilizing alkali metal or alkaline earthmetal salts. The alkali metal or alkaline earth metal salt is preferablysodium carbonate, calcium carbonate, calcium hydroxide, magnesiumcarbonate, magnesium hydroxide, magnesium silicate, magnesium aluminateor aluminum magnesium hydroxide. Typically, such tablet formulationscontain about 10-30 weight % stabilizing alkaline earth metal salts.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise fromabout 02 weight % to about 5 weight % of the tablet, and glidants maycomprise from about 02 weight % to about 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallycomprise from about 0.25 weight % to about 10 weight %, preferably fromabout 0.5 weight % to about 3 weight % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouringagents, preservatives and taste-masking agents.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in Pharmaceutical Dosage Forms:Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, NewYork, 1980).

Consumable oral films for human use are typically pliable water-solubleor water-swellable thin film dosage forms which may be rapidlydissolving or mucoadhesive and typically comprise annealed amorphousatorvastatin, a film-forming polymer, a binder, a solvent, a humectant,a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agentand a solvent. Some components of the formulation may perform more thanone function.

The film-forming polymer may be selected from natural polysaccharides,proteins, or synthetic hydrocolloids and is typically present in therange of about 0.01 to about 99 weight %, more typically in the range ofabout 30 to about 80 weight %.

Other possible ingredients include anti-oxidants, colorants, flavouringsand flavour enhancers, preservatives, salivary stimulating agents,cooling agents, co-solvents (including oils), emollients, bulkingagents, anti-foaming agents, surfactants and taste-masking agents.

Films in accordance with the invention are typically prepared byevaporative drying of thin aqueous films coated onto a peelable backingsupport or paper. This may be done in a drying oven or tunnel, typicallya combined coater dryer, or by freeze-drying or vacuuming.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations for the purposes of the inventionare described in U.S. Pat. No. 6,106,864. Details of other suitablerelease technologies such as high energy dispersions and osmotic andcoated particles are to be found in Pharmaceutical Technology On-line,25(2), 1-14, by Verma at al (2001). The use of chewing gum to achievecontrolled release is described in WO 00/35298.

The following non-limiting examples illustrate the invention.

EXAMPLE 1 General Method for Stabilizing Amorphous Atorvastatin byAnnealing at Elevated Temperature(Continuous Mode)

Amorphous atorvastatin calcium was prepared by spray-drying according tothe procedure described in U.S. patent applications, commonly owned,Published US Patent Application 2005-0032880, Ser. No. 60/623,086. Thevials used in the example were commercially available source fromWheaton, Milville, N.J.

The amorphous atorvastatin calcium was loaded into 20 ml glass vials(approximately 1 g per vial), and heated at 100±5° C. for 1, 6, and 18hours in an oven. After heating, the powder was transferred from thevials to 15 ml amber screw-cap bottles, and set-up on stability at 50°C./20% RH. In addition, unannealed amorphous atorvastatin calcium, whichwas loaded in 15 ml amber screw-cap bottles, was placed on stability asa control.

Analysis

High Pressure Liquid Chromatography (HPLC)

The annealed amorphous atorvastatin calcium was analyzed for impuritiesand atorvastatin degradation products using HPLC, by evaluating theratio of peak integration compared to the total integrated peak areas.Thus, 27 mg of either control or annealed amorphous atorvastatin calciumwas wetted with 5 mL of tetrahydrofuran, followed by addition of asolution of 1:1 tetrahydrofuran: acetonitrile (v:v) to a total volume of50 mL. The material was analyzed by HPLC (Zorbax SB C8 column, 25.0cm×4.6 mm, HPLC: Hewlett Packard 1100 series, 20 μl injection volume,flow of 1.5 mL/min). The elution used a linear gradient starting from67:21:12 (v:v:v) and switching to 54:34:12 (v:v:v) of 0.05M ammoniumacetate buffer (pH 5.0):acetonitrile:tetrahydrofuran after 40 minutes(100% of the latter mixture after 55 minutes).

Solid State Nuclear Magnetic Resonance (SSNMR) Spectroscopy

Approximately 80 mg of sample was tightly packed into a 4 mm ZrO spinnerfor each sample analyzed. All spectra were collected at 293 K andambient pressure on a Bruker-Biospin 4 mm BL HFX CPMAS probe positionedinto a wide-bore Bruker-Biospin Avance DSX 500 MHz NMR spectrometer. Thesamples were oriented at the magic angle and spun at 15.0 kHz,corresponding to the maximum specified spinning speed for the 4 mmspinners. The fast spinning speed minimized the intensities of thespinning side bands. ¹⁹F solid-state spectra were collected using protondecoupled magic angle spinning (MAS) experiment. The proton-decouplingfield of approximately 65 kHz was applied. The probe background wasreduced by subtracting signal from interleaved scans, during which a ¹⁹Fpresaturation pulse was applied. Typically, 32 scans were collected oneach ¹⁹F MAS spectrum. The recycle delay was set to 15 seconds to ensureacquisition of quantitative spectra. The spectra were referenced usingan external sample of trifluoroacetic acid (diluted to 50% by volumewith H₂O), setting its resonance to −76.54 ppm.

Powder X Ray Diffraction (PXRD)

The X-ray powder diffraction pattern of amorphous atorvastatin calciumand annealed amorphous atorvastatin calcium was determined using aBruker D5000 diffractometer (Madison, Wis.) equipped with copperradiation (Cu K_(α)). Data were collected from 3.0 to 40.0 degrees intwo theta using a step size of 0.04 degrees and a step time of 1.0seconds. The divergence and scattering slits were set at 1 mm, and thereceiving slit was set at 0.6 mm. Diffracted radiation was detected by aKevex PSI detector. An alumina standard was analyzed to check theinstrument alignment. Data were collected and analyzed using Bruker AXSsoftware Version 7.0. Samples were prepared for analysis by placing themin a quartz holder. The sample is typically placed into a quartz holderwhich has a cavity.

Results

Stability data obtained for three annealed samples and the controlsample are graphically illustrated in FIGS. 1 to 4. It can be seen thatthe annealing resulted in some degradation as expressed in higher levelof two individual degradants (FIGS. 3, 4), total oxidation products(FIG. 2), and total degradation products (FIG. 1) at t=0 (first timepoint on FIGS. 1 to 4). However, after storage for 6 weeks at 50° C./20%RH, the level of degradants was lower in samples annealed for 1 and 6hours comparing with the control sample. In order to expressstabilization by annealing in a more quantitative term, relativedegradation rate constants, k_(rel), were determined from the datapresented in FIGS. 1 to 4. The k_(rel) were calculated using Eq. 1:k _(rel)=(k/k0)*100%  Eq. 1where k is the zero order rate constant for annealed samples, and k0 isthe zero order rate constant for the control sample; k and k0 weredetermined from the data presented in FIGS. 1 to 4.

The relative rate constants (k_(rel)) are given in Table 1. Relativerates below 100% mean that the degradation rate is slower for annealedsamples and can be used as a quantitative expression of thestabilization by annealing whereas numbers greater than 100 percentwould indicate destabilization. For example, the relative degradationrate for total degradation products for the sample that was annealed for18 hours was 66 percent (bolded and Italicized in Table 1); I.e., 34percent less than in the control.

TABLE 1 Relative degradation rate constants (k_(rel)) of amorphousatorvastatin calcium relative to control after annealing at differentconditions* Relative rate constant, (k/k0) * 100% Annealing total timeat 100° C., total oxidative degradant 1, degradant 2, hours degradantsdegradants rrt 1.67 rrt 2.16 0 hours 100 100 100 100 (control) 1 hour 7880 76 88 6 hours 74 68 60 79 18 hours  66 63 55 73 *k_(rel) = (k/k0) *100%. k is the zero order rate constant, and k0 is the zero order rateconstant for the control sample. k and k0 were determined from datarepresented in FIGS. 1 to 4. “rrt” means relative retention time

Overall, the lower level of degradants at the 6-week time point forsamples annealed for 1 and 6 hours (FIGS. 1 to 4), and lower rates ofdegradation in the annealed materials (Table 1) demonstrate thatannealing increased the thermal stability of atorvastatin calcium.

FIGS. 5 and 6 a-6 d indicate that the SSNMR and PXRD spectra of annealedamorphous atorvastatin samples were similar to a control sample ofunannealed amorphous atorvastatin calcium.

Summary of Example 1

Annealed amorphous atorvastatin is surprisingly more stable thannon-annealed amorphous atorvastatin. This is an example of amorphousatorvastatin calcium which is stabilized by annealing at elevatedtemperature (i.e. temperature annealing). As indicated in the stabilitydata included in Example 1, annealed amorphous atorvastatin calciumdegraded to some extent during annealing as expressed in higher levelsof two individual degradants (FIGS. 3, 4), as well as total oxidationproducts (FIG. 2) and total degradation products (FIG. 1) at t=0 (firsttime point on FIGS. 1 to 4). The structure of the two degradants aredepicted in Schemes 1 and 2. However, after storage for 6 weeks at 50°C./20% RH, the level of degradants was lower in samples annealed for 1and 6 hours compared with the control sample.

The stability of annealed amorphous atorvastatin calcium compared tonon-annealed amorphous atorvastatin calcium can be expressed in terms ofrelative degradation rate constants as summarized in Table 1 inExample 1. Relative rates below 100% mean that the degradation rate isslower for annealed samples and can be used as a quantitative expressionof the stabilization by annealing whereas numbers equaling or greaterthan 100 percent indicate destabilization. For example, the relativedegradation rate for total degradation products for the sample that wasannealed for 18 hours was 66 percent (bolded and Italicized in Table 1infra Example 1); i.e., 34 percent less than in the control.

The results summarized in Table 1 demonstrate that annealed amorphousatorvastatin calcium can be stored for longer periods than non-annealedamorphous atorvastatin calcium. Moreover, annealed amorphousatorvastatin calcium can be used to prepare pharmaceutical dosage formswith enhanced stability profiles as compared to dosage forms containingnon-annealed amorphous atorvastatin calcium.

EXAMPLE 2 General Method for Stabilizing Amorphous Atorvastatin byAnnealing at Greater than Atmospheric Pressure(Continuous Mode)

Spray-dried or freeze-dried amorphous atorvastatin calcium ispressurized to about 1 kBar at about 50° C. for about 30 min, about 1hour, and about 6 hours.

EXAMPLE 3 General Method for Stabilizing Amorphous Atorvastatin byMicrowave Irradiation(Continuous Mode)

Spray-dried or freeze-dried amorphous atorvastatin calcium is irradiatedwith microwave frequency of about 2.45 GHz, power of about 20 W to 120 Win a continuous mode range in time period of about 10 seconds up toabout 10 hours using Microwave Power Generator Model 520A (ResonanceInstrument Inc., 9054 Terminal Ave., Skokie, Ill. 60077). A circularreaction cavity is fabricated to meet the requirements of testingpharmaceutical samples.

EXAMPLE 4 General Method for Stabilizing Amorphous Atorvastatin byMicrowave Irradiation(Pulse Mode)

Spray-dried or freeze-dried amorphous atorvastatin calcium is irradiatedfrom about 1 minute up to about 10 hours with microwave frequency ofabout 2.45 GHz, power of about 20 W to 120 W in a pulse mode range for apulse time period of about 10 to about 600 seconds using Microwave PowerGenerator Model 520A (Resonance Instrument Inc., 9054 Terminal Ave.,Skokie, Ill. 60077). A circular reaction cavity is fabricated to meetthe requirements of testing pharmaceutical samples.

EXAMPLE 5 General Method for Stabilizing Amorphous Atorvastatin byUltrasonic Irradiation(Continuous Mode)

Spray-dried or freeze-dried amorphous atorvastatin calcium is irradiatedwith ultrasonic frequency of about 20 to 35 KHz, power of about 100 W to3000 W in a continuous mode range in time period of about 10 seconds upto about 10 hours, using The Ultrasonic Generator (Active UltrasonicsSarl, Pults-Godet 6A, CH-2000 Neuchatel, Switzerland). The instrumenthas 3 separate probes that generate the following frequencies ofultrasound: 20 kHz, 30 kHz and 35 kHz. Specially designed cup-horns arefabricated to meet the requirements of testing pharmaceutical samples.

EXAMPLE 6 General Method for Stabilizing Amorphous Atorvastatin byUltrasonic Irradiation(Pulse Mode)

Spray-dried or freeze-dried amorphous atorvastatin calcium is irradiatedfrom 1 minute up to 10 hours with ultrasonic frequency of 20 to 35 KHz,power 100 to 3000 watts in a pulse mode range for a pulse time period of10 to 600 seconds using The Ultrasonic Generator (Active UltrasonicsSarl, Puits-Godet 6A, CH-2000 Neuchatel, Switzerland). The instrumenthas 3 separate probes that generate the following frequencies ofultrasound: 20 kHz, 30 kHz and 35 kHz. Specially designed cup-horns arefabricated to meet the requirements of testing pharmaceutical samples.

EXAMPLE 7 General Method for Stabilizing Pharmaceutical FormulationContaining Amorphous Atorvastatin Ca by Ultrasonic Irradiation(PulseMode)

A pharmaceutical formulation containing amorphous atorvastatin calciumis irradiated from 1 minute up to 10 hours with ultrasonic frequency of20 to 35 KHz, power 100 to 3000 watts in a pulse mode range for a pulsetime period of 10 to 600 seconds using The Ultrasonic Generator (ActiveUltrasonics Sarl, Puits-Godet 6A, CH-2000 Neuchatel, Switzerland). Theinstrument has 3 separate probes that generate the following frequenciesof ultrasound: 20 kHz, 30 kHz and 35 kHz. Specially designed cup-hornsare fabricated to meet the requirements of testing pharmaceuticalsamples.

All publications, including but not limited to, issued patents, patentapplications, and journal articles, cited in this application are eachherein incorporated by reference in their entirety.

Although the invention has been described above with reference to thedisclosed embodiments, those skilled in the art will readily appreciatethat the specific experiments detailed are only illustrative of theinvention. Accordingly, the invention is limited only by the followingclaims.

What is claimed is:
 1. A process for annealing amorphous atorvastatincomprising irradiating amorphous atorvastatin with microwave at afrequency ranging from about 1 GHz to about 100 GHz and power of about 1watt to about 3000 watts either in a continuous or pulse mode for a timeperiod ranging from about 1 second to about 10 hours.
 2. The process ofclaim 1, wherein said amorphous atorvastatin is irradiated withmicrowave at a frequency of about 2.45 GHz and power about 10 W to about500 W in a continuous mode range for a time period of about 10 secondsup to about 10 hours.
 3. The process of claim 1, wherein said amorphousatorvastatin is irradiated from about 1 minute up to about 10 hours withmicrowave at a frequency of about 2.45 GHz and power about 1 W to about3000 W in a pulse mode range for a time period of about 10 to about 600seconds.
 4. The process of claim 1, wherein said amorphous atorvastatinis amorphous atorvastatin calcium.
 5. The process of claim 1, whereinsaid amorphous atorvastatin is admixed with a pharmaceuticallyacceptable diluent, carrier, or excipient prior to said irradiatingstep.
 6. A process for annealing amorphous atorvastatin comprisingirradiating amorphous atorvastatin with ultrasound at a frequencyranging from about 15 KHz to about 40 KHz and power of about 100 wattsto 4000 watts either in a continuous or pulse mode range for a timeperiod ranging from about 1 second to about 10 hours.
 7. The process ofclaim 6, wherein said amorphous atorvastatin is irradiated withultrasound at a frequency of about 15 KHz to about 40 KHz and power ofabout 100 W to 3000 W in a continuous mode range for a time period ofabout 10 seconds up to about 10 hours.
 8. The process of claim 6,wherein said amorphous atorvastatin is irradiated from about 1 minute upto about 10 hours with ultrasound at a frequency of about 20-35 KHz andpower of about 100 W to 3000 W in a pulse mode range for a time periodof about 10 to about 600 seconds.
 9. The process of claim 6, whereinsaid amorphous atorvastatin is amorphous atorvastatin calcium.
 10. Theprocess of claim 6, wherein said amorphous atorvastatin is admixed witha pharmaceutically acceptable diluent, carrier, or excipient prior tosaid irradiating step.
 11. The process of claim 1, or 6, wherein saidamorphous atorvastatin is treated with a plasticizer prior to or duringthe annealing process.